The focus of this renewal application is DNA sequence variation. Our goal is to continue to develop a mapping method known as direct IBD mapping and to study the pattern of meiotic recombination in humans. Altered recombination is associated with non-disjunction, the major cause of aneuploidy. First, direct IBD mapping is a method that allows identification of genomic regions shared between related individuals without marker-by-marker genotyping. Large DNA segments shared identical in sequence (likely representing IBD DNA fragments) between related individuals are enriched in a procedure known as genomic mismatch scanning. The selected DNA fragments are then mapped by hybridization onto a genomic DNA microarray. In the last several years, we have optimized the steps and created the necessary resources for direct IBD mapping. Next, we will validate the procedure by mapping the IBD regions shared between individuals in CEPH families and will streamline various steps so that direct IBD mapping can become a tool for high-throughput mapping. Second, stimulated by the work on direct IBD mapping, we have begun to characterize the pattern of meiotic recombination in humans. In this renewal application, we will expand the scope of the project to characterize the variation in human recombination rates and map the genetic determinants of this variation. This proposal has the following aims: 1. Develop direct IBD mapping, a high-resolution identity-by-descent mapping method that does not require genotyping. 2. Characterize natural variation in recombination rate in humans. 3. Map the genetic determinants of natural variation in total recombination rate in humans. We expect the results from this study will provide a robust mapping method that is more efficient than current methods. It will also give insights into the pattern of human meiotic recombination, a key process that contributes to genetic diversity and to risk of non-disjunction.